Transfusion registry and exchange network

ABSTRACT

Disclosed is a registry for candidate transfusion donors, which invokes an inventory management policy to create and actively manage lists of candidate donors in order to minimize imbalances between demand and supply across multiple regions and across multiple categories of donors and recipients. Together with a genotyping laboratory, the registry does targeted recruitment of prospective donors who are typed for a set of genetic markers relating to clinically relevant antigens including mutations of Human Erythrocyte Antigens (HEA), genetic variants of Rh, and possibly additional antigens such as HLA and HPA. The registry monitors incoming demand for transfusion antigen genotypes, preferably stratify the demand into a set of categories representing stable subpopulations, and will apply strategies, disclosed herein, to tune the composition of candidate donor lists to match the demand, thereby avoiding excess, and unnecessary, typing of candidate donors.

RELATED APPLICATIONS

This application claims priority to U.S. application Ser. No.11/092,420,filed Mar. 29, 2005.

BACKGROUND

The matching of an extended set of significant antigens (ExtendedMatch™)will minimize adverse transfusion reactions (see Hillyer et al., BloodBanking and Transfusion Medicine; published. by Churchill Livingston,Philadelphia Pa.) and other potential complications arising fromallo-immunization. This is so particularly for patients receivingmultiple transfusions who, as in the case of hemoglobinopathies, mayotherwise become refractory to transfusion. However, the virtuallyexclusive current practice of invoking serological methods to determineantigen phenotypes, one at a time, creates considerable logistical andeconomic challenges for the effective implementation of this standard.Thus, the use of serological typing methods to identify large numbers ofprospective donors with a desirable repertoire of major and minortransfusion antigens so as to support diverse inventories of bloodproducts will require a substantial investment of both time andresources, especially given the increasing expense for increasingly rareserological reagents. Further, in part reflecting this investment, thecost of acquiring such units, typically priced to include a surchargeper desirable antigenic marker matched per unit, can be prohibitive. Theprocurement of matched blood for recipients, who either display anuncommon antigen or lack a common antigen, is particularly problematic.While collections of transfusion donors with rare minor blood groupphenotypes have been initiated (see the Redcross website), they remainlimited, for example with currently only 30,000 donors registered in theAmerican Rare Donor program.

Recent technological innovation (Hashmi et al., Transfusion, 45, 680-688(2005)) has the potential to enable the replacement of serologicalmethods of transfusion antigen determination by methods of geneticanalysis. These methods would not only obviate the need for rare andexpensive serological reagents but also would permit the concurrent(“multiplex”) analysis of an entire set of genetic determinants oftransfusion antigen phenotypes. Large-scale multiplexed transfusionantigen genotyping, particularly when combined with non-invasivecollection of samples such as “finger sticks” or buccal swabs, wouldprovide a basis for rapidly surveying donors for an extended set ofclinically significant antigens and to construct a diversified inventoryprior to collecting, processing and storing blood products.

The concept of a candidate donor inventory previously has beenimplemented in the form of bone marrow donor registries which have beenorganized around the world to provide a diverse pool of candidate donorswho can be genetically matched to patients by comparing the relevantgenetic loci within the Human Leukocyte Antigen (HLA) complex. However,in view of the highly variable nature of the HLA gene complex, theseregistries, in order to ensure a finite probability that a request for aspecific HLA type can be filled, must acquire and maintain a largeinventory by “taking all corners” Yet, by the same token of geneticdiversity within the HLA complex, the likelihood of any donor beingcalled upon is small, repeat donation exceedingly rare, and inventoryturnover low. In view of the substantial expense of recruiting andtyping prospective bone marrow donors, the operation of suchrepositories in an economically viable manner is difficult at best, andin fact, generally requires public expenditure (as in the case of theNational Marrow Donor Program, see their website) or privatephilanthropy (as in the case of private registries maintained byfoundations around the world).

In contrast to bone marrow and organ donation, blood donation isrelatively painless, and is performed in high volume, at an annual rateof approximately 50 million donations worldwide, routinely includingrepeat donation, creating high turnover in existing supplies of bloodproducts. The introduction of large-scale genetic typing intotransfusion diagnostics would permit a systematic increase in thediversity of the inventory to support an ExtendedMatch strategy in apractical and cost-effective manner. A diversified inventory in turnwould permit the rapid selection of a donor for a recipient with knowntransfusion antigen genotype (TAG) by genetic cross matching (see U.S.application Ser. No. 11/298,763, incorporated by reference).

The selection of compatible candidate blood donors in response torequests posted to a registry of such donors would facilitate the timelyprocurement of compatible blood products. This would be desirable inorder to improve the public health and to minimize the cost accruing inthe health care system in the form of unnecessarily prolonged hospitalstays and adverse clinical effects arising from the administration ofincorrectly or incompletely matched units of blood products such as redcell or platelets.

The operation of a transfusion donor registry of diverse composition and“critical mass” in a commercially viable manner calls for an effectiveorganizational architecture and for strategies of optimal inventorymanagement that represent a departure from the passive repositoryconcept.

SUMMARY

The invention discloses strategies for the creation and commerciallyviable operation of a diverse registry of candidate transfusion donors,preferably within a transfusion registry and exchange network (TRXN). Asdescribed herein, the registry invokes an inventory management policy tocreate and actively manage lists of candidate donors in order tominimize imbalances between demand and supply across multiple regionsand across multiple categories of donors and recipients. The registrymonitors demand and manages supply, preferably by forming a commercialalliance with (or by operating its own) genotyping laboratory, bytargeted recruitment of prospective donors who are typed for a set ofgenetic markers relating to clinically relevant antigens includingmutations of Human Erythrocyte Antigens (HEA), genetic variants of Rh,and possibly additional antigens such as HLA and HPA.

To permit the determination of actual strategies (or “policies”), ofmanaging the registry's inventory under various conditions, the registrydescribed herein operates as an actively managed buffer between thefluctuating demand and the procurement of supply by directed recruitmentof candidate donors to be placed into the list(s). The registry willmonitor incoming demand for transfusion antigen genotypes, preferablystratify the demand into a set of categories representing stablesubpopulations, and will apply strategies, disclosed herein, to tune thecomposition of candidate donor lists to match the demand. Methods ofstratifying demand into a set of known, stable subpopulations also aredescribed, as are strategies for directed recruiting of prospectivedonors, preferably by way of non-invasive sample collection

The demand, in the form of requests posted by member institutions forunits needed instantly as well as in the form of units reserved forlater use, generally will display regional imbalances and, at any onelocation, generally will fluctuate in time. The invention disclosesstrategies of operating the registry so as to maximize the probabilityof fulfilling the set of requests received at any one time—that is, tominimize the probability of failing to procure a set of donors who aregenetically compatible with the set of requests—under the constraint ofa preset budget.

Genotyping of prospective donors represents a principal contribution tothe cost of operations. The identification, characterization andrecruitment of donors with special and thus generally less commonphenotypes (and corresponding genotypic attributes) requires specialeffort and corresponding expense, and fully characterized blood productsfrom such donors generally command premium prices. It will be a specificobjective of the registry to maintain a list of such special donors. Tothat end, certain strategies are disclosed for improving upon randomsampling in identifying donors with special phenotypes by stratificationof the donor population into stable sub-populations. The optimaldesirable composition of the list(s) matching the anticipated demandacross a set of categories dictates the fractional allocation of fundsavailable for genotyping stratified subpopulations.

The registry disclosed herein generates revenue by issuing to its memberinstitutions including hospital transfusion services and traditionaldonor centers, the “permission to call” specific donors. That is, amember institution can acquire the right to call upon a specific donor,for one or more blood donations over a specified period, and perhaps forspecific application of derived blood products. Several arrangements andcorresponding pricing options including the analog of license androyalty payments are disclosed. There is a “flat” pricing model forunits selected under ExtendedMatch criteria in order to facilitateplacement of such units to generally greater clinical benefit to therecipient. Further, there are methods of providing incentives toencourage repeat donations from donors with desirable TAG attributes,including equity participation and/or profit sharing by individuals orcommunity organizations.

In addition, the registry gains revenue by charging fees for membershipas well as for services such as searches applying cross-matching rules(U.S. application Ser. No. 11/298,763, incorporated by reference) andfor providing a forum for member institutions to trade the“permission-to-call” licenses among one another. Preferably, theregistry also can provide access to linked inventories of linkedinventories of typed units of donor blood (“actual” units) maintained byits member institutions, thereby creating a larger potential market forproviders, and a larger product selection to users. In addition, theregistry can offer ancillary services such as transaction management(see U.S. application Ser. No. 11/092,420, incorporated by reference)including on-line “genetic cross-matching, to identify available(“callable”) compatible donors on its list. Rules relating to theselection of compatible donors under conditions of varying stringencyare disclosed in U.S. application Ser. No. 11/298,763.

Revenue generation is determined by the probability of being able tomatch requests submitted to the registry reflecting the inventorypolicies of member institutions—which in turn reflect requirements fromwithin a population of recipients of known genotype distribution andcertain actuarial risk profile relating to the occurrence of accidentsand need for surgical procedures. This probability in turn depends onthe size and composition of the registry. Within the framework ofdynamic programming, the evolution in time of candidate donor list(s)within this buffer is managed to reflect the events that affect the listcomposition, including: acquisition of new candidate donors, selectedfrom the set of such genotyped donors accepted into the list;re-acquisition of donors released from “permission to call” agreementsby member institutions; and placement of compatible or desirable(potentially compatible) donors into permission-to-call agreements withmember institutions attempting to manage their own respectiveinventories; as well as the gradual loss of callable donors who becomeunavailable.

Preferably, the registry forms part of a transfusion registry network(TRN), in the form described, which would ensure effectivecommunication, and would create an effective forum for exchange ofproducts and services between providers (“sellers”) and users(“buyers”), both members of the network. To maximize the clinicalbenefit of a transfusion registry network, particularly under aExtendedMatch paradigm, the network must offer access to a diversepopulation of donors reflecting the wide range of geneticcharacteristics of a diverse population of recipients.

Glossary:

-   “List”≡a list of active callable donors;-   “Registry”≡a list of active donors plus “dormant” but callable    donor.-   “Availability” means the exclusive right of use is available; in the    other words, list is also the real-time inventory maintained at TRN    IT department.-   “Callable donor”≡a collection of information of a donor including    identity, address, callability, genotype, blood type, and other    relevant information.-   “Callability”≡an indicator of a donor measuring his/her willingness    to donor one unit of blood next time, 0<callability≦1.-   “Not callable”≡a situation when a donor is not active for donation    and removed from the “list”, i.e., callability=0.-   “Blood type”≡a combination of the presence of antigens or the    absence of antigens (antigen negatives) in donor's blood.-   “Category”≡a collection of people with stable fractions of    sub-populations (ethnicities). Category can be demographic, such as    local community, or birthplace, or genotype such as HLA types, etc.

Parameters and Variables Part 1: Cost Parameters I.

-   K=fixed cost to start a typing program (such as planning and setup    fees).-   v=frequency of a blood type.-   c^(t)=typing cost per perspective donor (fixed).-   c^(d)=typing cost rate per callable donor (varies depending on    active management).-   c^(r)=cost rate for initial acquisition costs.-   h^(r)=additional holding cost rate for callable donor inventory at    donor centers.-   p^(r)=penalty cost rate for backorders at donor centers.

Part 2: Logistic Parameters

-   α=discount rate (one period) of cash, 0≦α≦1.-   L=lead time of a typing program.

Part 3: State Variables.

-   u=one-period demand for callable donors, a nonnegative random    variable.-   u^(b)=one-period demand for blood units, a nonnegative random    variable.-   w^(d)=inventory level of callable donors in the List.-   x^(r)=pooled inventory level of callable donors at donor centers.-   μ=    u    <∞.-   μ^(b)=    u^(b)    <∞.-   y^(i)=outstanding typing program initiated i periods ago, i=1, . . .    , L.-   ŷ=(y¹, . . . , y^(L)).

Part 4: Decision Variables.

-   z=pooled order size from donor centers to TRN-registry.-   y=internal request size from TRN-registry-IT to TRN-registry-Lab.

Part 5: Auxiliary State Variable.

-   v^(d)=echelon inventory held in the system, i.e., donor center pool    and the TRN-registry. From this definition, the echelon inventory    equals

v ^(d) =x ^(r) +w ^(d).

Part 6: Index.

-   n=the number of periods remaining until the end of the planning    horizon.

Part 7: Some Constraints

y≧0, z≧0, x ^(r) +z≦v ^(d) +y ^(L).

Part 8: Cost Parameters II.

-   β=natural decay rate of one callable donor unit over one period,    0≦β≦1.-   γ=decay rate of one callable donor unit per usage, or per blood unit    acquired, 0≦β≦1.-   ε=fraction of revenue payable from donor centers to registry per    blood unit sold per callable donor unit held at donor centers.-   η=fraction per excess callable donor unit the donor centers    considered selling back to the registry.-   x_(c)=critical callable donor inventory level, above which donor    centers will consider selling a fraction of excess callable donors    back to registry.-   ρ=revenue from sells per unit blood at donor centers.-   ρ^(b)=buy-back revenue per callable donor unit at donor centers.

DESCRIPTION OF THE FIGURES

FIG. 1 depicts cross-matching probability of finding at least one andtwo phenotype-matched donors in two homogenous populations.

FIG. 2 depicts a scheme for organization of a transfusion registrynetwork(s) (TRN), with hospitals, donor centers, patients and candidatedonors, where the cross-matching of donors and recipients is carried outwith genetic cross-matching (gXM) of genotypes.

DETAILED DESCRIPTION Section 0: Managed Donor List and ManagementPolicy—The Case of Identical Donor and Recipient Populations

A problem in a registry as described herein is to determine the optimalsize of a candidate donor pool (to maximize the probability of having amatch with recipients, yet reduce the costs associated with typingcandidate donors) within a single homogenous or at least stable (“fullystratified”) population identical to that of the recipient(s). Thesolution, given a distribution of phenotypes—and that of the underlyingtransfusion antigen genotypes, the matching probability (under aspecified compatibility criterion—either an exact match or a match underthe relaxed matching criterion, where the donor does not express anyantigens not expressed by the recipient; see gXM application)—across-match probability is readily calculated—this provides the basisfor determining the optimal number of donors from the same populationthat best fulfills transfusion demand without costly excess screening.

Probability of finding at least n donors of a certain blood type(indexed by l or the l-th type) in a randomly sampled donor set from thesaid population

${c_{l}^{d} = {{c_{l}^{d}\left( {y,\theta,C_{\max}} \right)} = {\frac{C^{*}}{\sum\limits_{l}y_{l}}\frac{v_{l}^{- q}}{\sum\limits_{l}v_{l}^{- q}}}}},$

where parameter N is the size of a donor sample and fi is the frequencythe blood type. The summation is from 0 to n-1.

EXAMPLE I Effect of Donor Set Size and Recipient Blood Type on theProbability of Finding at Least n Donors

It is clear that screening donors adds cost, but also thatunder-screening can result in donors not being available to fill demand,which results in revenue loss. Thus, it is beneficial to balance andarrive at a minimum number screened, so as to reduce cost, but maintainadequate inventory.

EXAMPLE I Illustration of Donor Sample Size Effect on Cross-MatchingProbability in a Homogenous Population

FIG. 1 illustrates the cross-matching probability of finding at leastone and two phenotype-matched donors in two homogenous populations,Chinese and Israeli. One particular phenotype—Do(a+b−)—is considered inthis example. Occurrence frequencies of this phenotype in Chinese andIsraeli populations are respectively 1.26% and 16.56%. Those frequencieswere determined by genotyping a number of donors. Obviously the moreabundant the phenotype in a population, the higher the chance of findingmatches; and, the larger the sample size, the higher the chance.

Probability of fulfilling a set of requests from recipients randomlyselected from a given homogeneous (or “stable”) population, as afunction of the size of a donor pool randomly selected from the samepopulation

${\Pr \left( {\left. {x \geq n} \middle| N \right.,f_{l}} \right)} = {1 - {\sum\limits_{j = 0}^{n - 1}\; {\begin{pmatrix}N \\j\end{pmatrix}{f_{l}^{j}\left( {1 - f_{l}} \right)}^{N - j}}}}$

where N_(r) and N_(r) are recipient sample size and donor sample size,respectively, and f_(l) is the frequency of the l-th blood type.

Active inventory management is the practice of matching inventory toaverage anticipated demand (as opposed to blindly maximizing inventory,thereby ensuring that requests will be met with high probability, butreducing turn-over, thereby incurring a low return on the initialinvestment of gTyping an excess number of candidate donors), which leadsto the optimal solution. Maintaining inventory at a certain presetmultiple of anticipated average demand is most desirable.

Demand for particular bloodtypes will vary based on factors includingthe genetic distribution of the relevant blood group antigens in eachlocal recipient population. Where increased demand for certainbloodtypes is anticipated, stratification of donor populations such thatthose representing a larger proportion of such bloodtypes areidentified, can be used to maintain demand/supply balance.

Section I: Right-to-Call Pricing and the Value of Repeat Donors

Candidate donors with desirable transfusion antigen attributes—generallyimplying premium pricing of blood products—are particularly valuable asrepeat donors since no additional genotyping is required—this concept isnot part of current blood bank pricing policies. Thus, simply selling anassay permitting genotyping may under-represent the potential futurevalue of information derived by application of the assay. On the otherhand, excess cost will be incurred.

The solution is a “right-to-call” pricing model, connecting price andcost of operations, most notably the cost of genotyping, which isfurther connected to transfusion antigen genotype (TAG) frequencies inthe population and other factors. This pricing model is distinct fromcurrent methods where pricing is based on irrelevant parameter—e.g., thenumber of antigen negatives, that discourages efficient registrymanagement and utilization of resources.

The “right-to-call” pricing structure would typically include an upfrontpayment (“access fee”), a periodic payment for the continued (de factoexclusive) right to call, and a fee based on the fraction of recurringrevenue from sales of blood products derived from a specific donor. Inreturn for undertaking a screening program at its own expense, hence atits own risk, a registry can identify candidate donors with specialattributes. In return for having made an investment and having acceptedthe risk, the registry, when conferring upon a producer or distributorof blood products the right to call upon such a donor, can charge anupfront (“access”) fee, a fraction of all revenue derived by theproducer or distributor from such a donor (“royalty”) and a periodicpayment while the producer or distributor—in accordance with its owninventory policy—holds the right to call upon said donor, said periodicpayment reflecting the registry's inability to generate revenue fromconferring to a third party the right to call upon said donor. The sizeof the periodic payment can be based on the loss of revenue otherwisegenerated in the form of an access fee and royalty payments charged to athird party (periodic payment must be sufficiently high to deterproducer from simply “shelving” the callable donor).

As an alternative, donor centers may choose to sell excess inventory ofcallable donors back to the registry, allowing sharing of donorinformation, or may elect to list excess inventory for sale to otherparticipating donor centers by way of transactions hosted by theregistry.

Pricing and the Standard of Clinical Care

The relationship between pricing strategies and standards of medicalcare. It is clear that mismatches in some blood group antigens are moreclinically significant than others (see U.S. application Ser. No.11/298,763). The more clinically significant antigens cannot be asreadily mismatched. The price for obtaining blood which can match suchantigens is related to the amount of effort required to obtain theproduct, which has to do with occurrence frequency of that product inthe population.

The intrinsic value of one callable donor unit is related to the amountof effort invested for searching. If a blood type is rare, the price isusually higher. The price ρ_(l) of one unit of blood of type l isapproximately ρ_(l)≈ρ_(o)+ρ₁v₁ ^(−q), where q is a constant and 0≦q≦1.Before T periods later, when one callable donor unit is fullydepreciated, the total potential value per such unit is:

π₁≈c^(r)+ερ_(l)T.

The cost per callable donor unit can be represented by:

${\Pr \left( {FF}_{l} \right)} = {{\Pr \left( {\left. {x_{r} \leq x_{d}} \middle| N_{r} \right.,N_{d},f_{l}} \right)} = {1 - {\sum\limits_{i > j}{\begin{pmatrix}N_{r} \\i\end{pmatrix}\begin{pmatrix}N_{d} \\j\end{pmatrix}{f_{l}^{i + j}\left( {1 - f_{l}} \right)}^{N_{r} + N_{d} - i - j}}}}}$

with nonnegative constant q specified above, and the price per unitcallability is related to the cost per unit by some scaling factor plusa price offset which can be either markup or markdown in order to matcha demand curve:

p_(l)˜k·c_(l) ^(d)+offset

Where bloodgroup determinants are typed in a “multiplexed” assay, whichtypes a variety of bloodgroup determinants including those resulting inantigens having greater clinical significance, this avoids creating adisincentive to typing of antigens having greater clinical significance,as would occur in serotyping—where additional antigen typing candramatically increase typing cost.

Section II: Active Management of a Donor Registry by “Optimal Mixing”Problem: as demand for blood fluctuates over time (that is, from periodto period), imbalances may develop between demand and supply—randomsampling becomes ineffective, because random donor sample may notreflect the actual blood type distribution in the demand and thus causeovertyping of donors and waste of resources. In addition, geographicalimbalances between demand and supply will exist that remain stable overtime.

Having introduced the concepts of a guided selection of candidatedonors, and conferring a right to call upon available (“qualified”)candidate donors and right-to-use fees, for the special case of a fullystratified population, it is now helpful to generalize to a situation,encountered in practice, characterized by an imbalance between thenumber of requests received per period from within a specific category(“fluctuating demand”), and the number of callable donors from withinthat category available to match those requests. The optimal strategyfor active management of a registry in handling imbalances in“same-category” demand and supply calls for “optimal mixing” ofcandidate donor s selected from multiple available categories (e.g.,African-Americans, Asians), each such category characterized by a set ofantigens (and corresponding underlying transfusion antigen genotype)frequencies, and possibly other factors such as the readiness to donate.

Consider the function of the registry to maintain an actively managedlist of candidate donors which is “not too small” and “not too large.”In that list, each entry consists of the identity, genotype, and(corresponding) blood type of a donor, the blood type preferably in theform of a binary string representing the presence or absence of specificexpressed transfusion antigens. (see gXM application). In addition, eachentry also is assigned a “category” (“slot”) which relates to thedistribution of transfusion antigen genotype (“TAG”) frequencies andrelated factors, such as actuarial factors, affecting the availabilityof candidate donors in that category. The numbers of callable (oractive) donors in the slots represent the “inventory levels” at the TRN.Donors maintained in the list can also be inactive. Inactive donors canbe those who are not available or reachable—these entries, after sometime and in accordance with certain criteria—are removed from the activedonor list or the inventory.

At any particular time, the number of requests from within a specificcategory may exceed the inventory of callable donors from within thesame category. Maintaining an optimal inventory in such a situationcalls for an optimal “mix” of candidate donors across multiplecategories. A category, for example, can be a specific homogeneouspopulation within the proximity of a specific blood bank client of theregistry, or can be a demographic segment within a certain “stable”population (of known TAG frequencies). As discussed below, registrysearches can be organized to return candidate donors per category, forexample, availability at the nearest collection site.

The optimization problem relating to the general case is formulated inSection III by mapping it to the determination of the optimal inventorymanagement policy for a 2-echelon model; it is shown that an optimalsolution exists.

Section III: Operation of an Actively Managed Donor Registry

Often times, consulting the TRN may be more appealing for the immediateaccess to a greater selection of callable donors. For example, one donorcenter may “deposit” the availability of callable donors and an “order”requesting donor info of the same blood type can be “filled” via thenetwork. Information sharing benefits both patients and serviceproviders. Data centralization and “exchange” functionality of the TRNallows expansion of the network, and economies of scale will be readilyassessable. The real-time aggregate demand and supply also provides thedirect affiliates within the network a unique opportunity to forecastand better administer their donor recruiting programs.

111.1 Functional Organization

The TRN would actively managed the list (“buffer”) between fluctuatingaggregate demand in the form of pooled recipient requests and supply inthe form of candidate donors recruited and TAG-typed at a laboratory,and would respond to specific requests from the list manager specifyingoptimal mixing ratios across specific donor categories.

Receiving and Processing Requests within a Network—A request for aparticular blood product typically is initiated by a hospital on apatient's behalf. The patient's genotype and so-derived blood type aresent to the donor center. If a matching unit is found in the donorcenter's own inventory of blood products, it is delivered. If nomatching unit is found, the donor center subscribing to the services ofa TRN (such as that disclosed in co-pending application Ser. No.11/092,420) may take one of two actions—it may look up a local list ofcallable donors and make arrangement for blood donation, or it may posta request for a unit of particular blood type on a listing hosted at theTRN.

All interested parties, including peer donor centers within the TRN, areable to view the listing and compete to fulfill the request, forexample, by bidding (in accordance with an auction or other mechanism,see below) the winning donor center owns the right to deliver the unit.The mechanism of listing and bidding, preferably hosted at TRN's networksite, such as a password-protected world-wide-web (WWW) site,facilitates competition and enables an efficient way of utilizing bloodresources.

Donor centers, in order to replace blood units delivered in response torequests, may consult the registry to identify local callable donors andmay elect to call upon such donors for donations.

Demand Monitoring by the List Manager—While fluctuations in demand atindividual donor center may be large and random, the aggregate demandmay display a smaller stochastic component. The reason is that, ahospital may choose to send request for a specific blood unit to any oneof the available donor centers. If those centers are linked to a commonregistry network, demand fluctuations are distributed across the entireset of member institutions. Problem: predictability of demandfluctuation.

The solution is to pool demand by monitoring demand pattern in acentralized blood unit exchange. “Noise cancellation” would improvedemand distribution prediction and facilitate development of optimalpolicy in inventory control. Callability is generally reserved fordonors who have been genotyped but have not actually donated blood.

Replenishing the List: Donor Callability Status—This circle related tothe handling and usage of blood product reduces “callability” of donorson the lists at donor centers. Again, the “callability” is an indicatormeasuring a donor's willingness to donate one unit of blood uponrequest. The value of callability is between 0 and 1. A value of zeromeans the donor is not callable and thus is removed from the list. Ifone adds up callability values of all donors in each category, the sumrepresents a measure of the level of a local inventory of qualifieddonors. If this level drops below some threshold, the center willattempt to replace the “spent” callabilities, by either identifying andtyping qualified donors by itself or purchasing information units from aTRN of which it is a member.

A TRN, organized in accordance with the present invention, hosts aninformation-technology (IT) division which maintains a list of callabledonors, provides cross-matching (xM) and bidding services to the donorcenters, and generates requests for qualified donors. The TRN also has arelationship with a diagnostic laboratory, which directs selection ofcandidate donors and manages g-typing programs. The laboratory can bepart of the TRN, for example, as a division, or it can be a TRNaffiliate, funded by the TRN and/or other public expenditure.

Genotyping as a method of erythrocyte antigen typing and blood typedetermination makes it possible to separate—in time and in space—theprocesses of targeted recruiting of candidate donors; making thebloodtype determination (for example in an affiliated laboratory); andcollecting and processing the actual blood;

The submission preferably takes place via an interface such as awebsite. Upon receiving a request, the user interface sends a request tothe database management software at IT division of the TRN. The softwarelooks up the active donor list, locates suitable donor(s) of therequested blood type(s), and then returns the information fordownloading.

III.2 Transactions-Flowchart III.2A Typical 2-Party Transaction:

Requesting Entity (Location A):

TheRegistry

III.2B 3-Party Transaction without Delay:

Requesting Entity (Location A):

TheRegistry (Location B):

Field Collection Unit (Location A)

Requesting Entity (Location A):

-   -   Receive or anticipate request for specific blood type(s) place        request to REGISTRY for specific bloodtype

TheRegistry (Location B):

receive and process request (via gXM Engine); IF MATCH in ActivelyManaged Donor List (AMDL) {  notify donor;  schedule collection (localProcessing Entity, or Field Collection  Unit);  manage shipment of unitto Requesting Entity; } ELSE (“out of balance supply”) {  notify closestField Collection Unit;  trans-ship sample to selected genotypingpartner;  notify donor;  schedule collection (local Processing Entity,or Field Collection  Unit);  manage shipment of unit to RequestingEntity; }III.2B 3-Party Transaction with Delay (“Scheduled Delivery”):

Requesting Entity (Location A):

TheRegistry (Location B):

Processing Entity (Location A)

III.3 Operating an Actively Managed Donor List: Optimal Inventory Policy

An active donor list at TRN can be viewed as a separate “virtual”inventory operating in tandem with an inventory of all local listscombined.

The optimal inventory policy at the registry is designed to absorbfluctuations in demand, in the form of the aggregate of requestsgenerated by donors centers within the network. The active donor list atthe registry is maintained in accordance with the optimal inventorypolicy by the registry's IT division which forwards requests for typingof new candidate donors to the diagnostic laboratory affiliate whichorganizes typing programs in order to fill the requests.

To develop an optimal inventory policy for an actively managed registryhandling the general case of demand-supply imbalance within the contextof a network of interacting parties participating in the procurement oftransfusion products, consider a registry as an element of a transfusionnetwork. Such a transfusion network can be organized as illustrated inFIG. 2, comprising major entities including transfusion registrynetwork(s) (TRN), donor centers, hospitals, patients and candidatedonors.

Optimal Inventory Policy

A TRN preferably co-hosts listing and bidding services for blood unitexchange among the donor centers. Since the requests for callable donorsreflects the requests for blood units after some time delay, atransfusion network may explore this correlation and improve itscapability of predicting near-term overall demand for callable donors.

Actively Managed Buffer:

Inventory control coordinates demand (hospitals), retail inventory(donor centers), and warehouse inventory (registry) revenue. Best policyof recruiting and typing qualified donors depends on demanddistribution, gXm, inventory levels, and cost per unit qualified donorunit quoted from affiliated lab.

Formulation of the optimization problem—minimize δ_(PxM) at a givencost, and write down appropriate evolution equations to map onto dynamicprogramming and 2-echelon inventory models. (Buffers: blood center,registry).

Some assumptions—To simplify an callable donor inventory at a donorcenter, we assume donor centers can always manage to replenish bloodinventory level shortly after units are delivered before they furtherrequest donor contacts from a donor registry. Dynamics of inventorylevel at donor centers should also take into account the decrease inexcess inventory due to the buy-back program at the registry.

Cost in the system—Suppose a donor registry serves more than one bloodcenter, the pooled cost includes the fixed cost of subscription fee(A^(s)) and one-period expected penalty and holding (licensing) costs.If there is negligible variable cost of information delivery, thesystem-wide variable holding cost is negligible and only cost is penaltycost, that is p^(r) E[u−βx^(r)−z]⁺. Besides holding cost (licensing),other expected costs include initial acquisition cost and cost due tosales of blood unit drawn from the callable donors at hand (loyalty).The total expected cost is expressed as:

${E\left( {{\left\lbrack {{c^{d}\left( {y,\theta,C_{\max}} \right)} + \Delta} \right\rbrack z} + {ɛ\; u^{b}}} \right)} = {{\left\lbrack {{c^{d}\left( {y,\theta,C_{\max}} \right)} + \Delta} \right\rbrack z} + {\frac{ɛ}{\gamma}{\mu.}}}$

On the other hand, system-wide expected costs related to setup andtyping acquisition

A finite-horizon dynamic program—A dynamic program, ĝ_(n)({tilde over(y)}, v^(d), x^(r)), can be formulated to address minimum totaldiscounted expected costs with n periods remaining, if the system beginsfrom some initial state ({tilde over (y)}, V^(d), X^(r)), excluding allthe fixed costs . . .

Existence of Solution—Following footsteps of Clark and H. Scarf,“Optimal Policies for a Multi-Echelon Inventory” Problrm. Mgmt. Sci. 6,475-490 (1960), the problem is decomposed into a pair of sub-problems,which also makes it more relevant to the interest of donor centers. Thefirst of the sub-problems involves donor center pool alone: Since R()is a convex function and adding a linear function of a function doesaffect the its convexity, a critical-number policy solves this problem.

From system's standpoint, neglecting the cost encountered between donorcenters and TRN, which nets to zero, an induced penalty cost functionsmay be defined and a second dynamic program can be defined. Assume thedemand probability distribution peaks, the penalty function should be adecreasing function of and set to zero as becomes greater than acritical level x_(n) ^(r′) If the cost rate c^(d) such that it does notaffect the declining nature of the penalty cost at small y's, theminimization problem ĝ_(n) ^(d)({tilde over (y)}, v^(d)) clearly isconvex and an (s, S) optimal policy exists.

Basically, shifting the initial acquisition cost appropriately to theloyalty charges later on facilitates the transactions between donorcenters and the network and reduces the system-wide penalty of notfilling requests from transfusion recipients.

The general minimization problem is now decoupled into sum of twosub-problems that are solvable:

ĝ _(n)({tilde over (y)}, v ^(d) , x ^(r))=ĝ _(n) ^(r)(x ^(r))+ĝ _(n)^(d)({tilde over (y)}, v ^(d)),

and an optimal policy for the system consists of an optimal policy forĝ({tilde over (y)}, v^(d)) for the typing programs and a modifiedcritical-number policy for ĝ_(n) ^(r)(x^(r)) as the order policy fromthe donor centers.

The above formulation was derived for one blood type inventory and thebudget constraint C_(max) aims at a single blood type. In reality, manyblood types coexist in the inventory. The above formulation is stillvalid in this case, except C_(max) then stands for the budget constraintfor typing programs attempting to find qualified donors of more than oneblood type. The parameter θ will be introduced in the next section,which is related to the knowledge of stratified donor population. Itwill be seen the effect of the budget is reflected in the cost percallable donor, c^(d) , which takes part in the overall optimization ofthe current inventory control.

In a more general case: fluctuating demand from complex time-varyingpopulation→inventory control alone is not sufficient because demanddistribution can greatly differ from any homogenous distribution→callfor active management on supply side.

Active Management of Supply: “Optimal Mixing”

Problem: how to enhance representation of callable donors in view offluctuating policies of heterogeneous nature resulted from inventorycontrol?

Solution: selecting candidate donors and tuning inventory to minimizeper callable donor cost by active mixing of at least two populations(and typing based on a mixing ratio). The goal is to minimize overallcost per unit callable donor, c^(d), an implicit parameter in activedemand management, related to the typing policy, categories, and abudget constraint: c^(d)=c^(d)(y, θ, C_(max)), by way of directedsampling on the supply side.

The first step is to gain as much information as possible of thepopulations at hand. This step basically is to study the composition inthe donor populations or, in the other words, to “stratify” a stablepopulation into finer subpopulations, such as “pure” ethnicities or anyother relevant stable categories.

Knowing the bloodType distributions is a prerequisite—In donorpopulations, bloodtype distribution is a prerequisite and the only wayto arrive at an accurate result is by way of genotyping, so that aregistry network has thoroughly collected information about the donorpopulation. First of all, genotype frequencies of the sub-populations(ethnicities) are known, which are denoted by {_(jl)} with index l fordifferent genotypes and j for different sub-populations. The summationof {_(jl)} over all genotypes for any given sub-population is thusunity, or

${\sum\limits_{l}f_{jl}} = 1.$

We define ethnicity profile, which has been surveyed, for each category,indexed by i, as a set of mixing coefficients {c_(ij)}, which satisfies

${\sum\limits_{l}c_{ij}} = 1.$

Since the frequency of occurrence of bi-allelic combination is additive,one can calculate the genotype frequencies in any given category by wayof linear combination. We denote such frequencies with {θ_(il)} and thewhole set with θ. There is then

$\theta_{il} = {\sum\limits_{j}{c_{ij}{f_{jl}.}}}$

The frequencies of the sub-populations are time-invariant and thefrequencies of the categories may vary slowly over time but can bemonitored closely. Those observables are assumed known and not tunable.However, if sufficient genotype distribution in donor population isknown, in principle, one can adjust the sampling strategy on the donorpopulation so as to type and seek in the categories that are known to bericher in the genotypes of interest. Consequently, the overall typingcost of the qualified donors is lowered by directed sampling.

Formulate the problem—We introduce {ω_(i)} to denote a set of mixingcoefficients of the categories, or collectively by ω. Let the mixeddonor population be {v_(l)}. There is then

$v_{l} = {{\sum\limits_{i}{\omega_{i}\theta_{il}}} = {\sum\limits_{i,j}{\omega_{i}c_{ij}{f_{jl}.}}}}$

Since the sampled population has uncertainty, we need to express theprobability of completely filling (full-fill) of the requests (y_(l)).We denotes such probability Pr^(ff) and there is

${{\Pr^{ff}\left( {{y_{l}D},\omega,\theta} \right)} = {\sum\limits_{d_{l} \in {\lbrack{0,D}\rbrack}}{{\delta^{0 +}\left( {d_{l} - y_{l}} \right)}{\Pr \left( {{\xi = {d_{l}D}},v_{l}} \right)}}}},$

where D is the total size of donor population and function δ⁰⁺ () isdefined as

${\delta^{0 +}(y)} = \left\{ {\begin{matrix}1 & {y \geq 0} \\0 & {y < 0}\end{matrix},} \right.$

Then,

${\Pr^{ff}\left( {{y_{l}D},\omega,\theta} \right)} = {{\sum\limits_{d_{l} = y_{l}}^{D}{\Pr^{xM}\left( {{\xi = {d_{l}D}},{v_{l} = {\sum\limits_{i}{\omega_{i}\theta_{il}}}}} \right)}} = {\Pr^{xM}\left( {{{\xi \geq y_{l}}D},v_{l}} \right)}}$

where Pr^(xM) is a cross-match probability and can be approximated by abinomial distribution. The probability of fulfilling all y_(l) requestsof blood type l thus equals the probability of finding at least y_(l)qualified donors in D individuals drawn from a mixed population, inwhich l-th blood type has a combined frequency of v_(l). And thefunction has the form,

${{\Pr^{xM}\left( {{{\xi \geq n}N},f} \right)} = {{1 - {\sum\limits_{k = 0}^{n - 1}{\begin{pmatrix}k \\N\end{pmatrix}{f^{k}\left( {1 - f} \right)}^{N - k}}}} \approx {P\left( {n,{Nf}} \right)}}},$

which can approximated by an incomplete gamma function, P().

${{P\left( {a,b} \right)} \equiv {\frac{1}{\Gamma (a)}{\int_{0}^{x}{^{- t}t^{a - 1}{t}}}}} = {\frac{1}{\Gamma (a)}^{- x}b^{a}{\sum\limits_{k = 0}^{\infty}{\frac{\Gamma (a)}{\Gamma \left( {a + 1 + k} \right)}b^{k}}}}$

The intrinsic value of one callable donor unit is related to the amountof effort invested to search for it. If a blood type is rare, the priceis usually higher. The price ρ_(l) of one unit of blood of type l isapproximately ρ_(l)≈ρ₀+ρ_(l)v_(l) ^(−q), where q is a constant and0<q<1. Before T periods later, when one callable donor unit is fullydepreciated, the total potential value per such unit is:

π_(l)≈c^(r)+ερ_(l)T.

The objective of the active management is to tune the sampling of donorpopulation to minimize the probability of NOT realizing the full valueof the potential callable donor units under given budget constraint.Such probability can be expressed as:

${\delta_{\Pr}^{v}\left( {{yC},\omega} \right)} = \frac{\sum{{\pi_{l}\left\lbrack {v_{l}\left( {\omega,\vartheta} \right)} \right\rbrack}{y_{l} \cdot \left\lbrack {1 - {\Pr^{ff}\left( {{{y_{l}D} = \frac{C}{{\overset{\_}{c}}^{t}}},\omega,\vartheta} \right)}} \right\rbrack}}}{\sum\limits_{l}{{\pi_{l}\left\lbrack {v_{l}\left( {\omega,\vartheta} \right)} \right\rbrack}y_{l}}}$

where c ^(t) is the averaged cost over categories, if typing programadopts different configurations of the typing tools among the differenttargeted categories, then

${\overset{\_}{c}}^{t} = {\sum\limits_{i}{\omega_{i}{c_{i}^{t}.}}}$

We denote optimal probability above {circumflex over (δ)}_(Pr) ^(v) anddefine the following optimization problem:

${{{\hat{\delta}}_{\Pr}^{v}\left( {y,\theta,C_{m},\delta_{th}} \right)} = {\min\limits_{\omega}\left\{ {{{\left\lbrack {{\delta_{\Pr}^{v}\left( {{yC},\omega} \right)} - \delta_{th}} \right\rbrack^{+}\text{:}C} \geq 0},{\omega \geq 0},{{\sum\limits_{i}\omega_{i}} = 1},{C \leq C_{m}}} \right\}}},$

where δ_(th) is a threshold in percentage, e.g., 0.1%, and C_(m) is themaximum typing budget. If the optimal total cost is below this budgetlimit, the problem is to minimize δ_(Pr) ^(v), or if possible to make itbelow the threshold δ_(th). Otherwise, the problem is minimization ofδ_(Pr) ^(v) under total cost constraint, C_(m).

Prove optimal cost is the lowest cost—Let ω* and C* be solution of theabove optimization problem, namely, ω* denoting the optimal mixingcoefficients of categories and C* denoting the “optimal” cost.Intuitively, the so-calculated C* is “optimal” in the sense that it isthe minimal cost of arriving at any given δ_(Pr) ^(v). The proof is bycontradiction. Suppose the optimal cost is not minimal cost for a givenδ_(Pr) ^(v), there should exist a total cost C** (<C*) that achieve thesame δ_(Pr) ^(v). Then, instead of saving on the total cost by the netamount of C*-C**, we put it in use and type some extra prospectivedonors but concentrating on one existing category. The result: with thesame C*, we achieve a lower δ_(Pr) ^(v) with an effectively different,obviously better, ω**. This contradicts our assumption that ω* isoptimal.

The cost per callable donor unit can be then computed as:

${c_{l}^{d} = {{c_{l}^{d}\left( {y,\theta,C_{\max}} \right)} = {\frac{C^{*}}{\sum\limits_{l}y_{l}}\frac{v_{l}^{- q}}{\sum\limits_{l}v_{l}^{- q}}}}},$

with nonnegative constant q specified above. Interestingly, a smallervalue of p shifts the cost from extremely rare blood types to less rareones. By using appropriate pricing strategy, the system-wide utilityefficiency can be lifted. The averaged cost per callable donor is:

${\overset{\_}{c}}^{d} = {{{\overset{\_}{c}}^{d}\left( {y,\theta,C_{\max}} \right)} = \frac{C^{*}}{\sum\limits_{l}y_{l}}}$

Global optimization—an inventory model was formulated that handlesdemand fluctuation and non-zero delay in delivery of the typing results.We showed that optimal solutions exist to solve the inventory problem.However, the cost structure has to be decided together with the typingprograms. We then formulated the optimization problem that finds theoptimal mixing coefficients that best fulfills the request under budgetconstraints. This problem handles the uncertainty on the supply side,namely the donor population, by way of stratification and tuning. Thebest cost structure is then a negotiation parameter between the demandsolution and supply solution. By solving two solutions iteratively, onecan achieve global solutions.

In a case of an initial random mixed (patient) population, theoptimization problem is likely end up with a set of mixing coefficientssimply reflects the proportions in the mixing coefficients ofethnicities in the sample. As the registry operation continues, it islikely bloodtype distribution in the patient population follows apathway so that real-time composition deviates unpredictably from theoriginal one. In such case, a general global optimization routine shouldbe run in order to reach an optimized mixture of donors and asystem-wide low cost. An interesting case is unusually high occurrenceof rare bloodtypes may be easily cross-matched by looking into adifferent ethnicity or in a different region, in which such types aremore frequently represented—an action that is likely automatically takenby the optimization process.

It should be understood that the terms, expressions and examples hereinare exemplary only and not limiting and that the scope of the inventionis limited only by the claims which follow, and includes all theequivalents of the claimed subject matter.

1-26. (canceled)
 27. A method of operating an entity which provides identities of candidate blood donors selected to have particular antigen bloodtypes determined to be compatible to those of specific recipients to entities seeking such particular antigen bloodtypes, the method comprising: monitoring the number of requests received per period of operation for said particular bloodtypes; and periodically performing targeted recruiting and transfusion antigen genotyping of specific numbers of candidate donors within a particular sub-population of the candidate donor population, so as to minimize the probability of failing to fulfill a request for a particular antigen bloodtype.
 28. The method of claim 27 wherein the total cost of targeted recruiting and genotyping of prospective candidate donors for every request fulfilled is minimized.
 29. The method of claim 27 wherein operations are performed so that the number of candidate donors remains constant.
 30. The method of claim 27 wherein operations are performed in a manner ensuring—an increase in the number of genotyped candidate donors by reinvestment of proceeds under a condition of maintaining zero profit.
 31. The method of claim 27 wherein the antigen bloodtypes represent clinically significant phenotypes.
 32. The method of claim 27 wherein compatibility is achieved when there is an exact match between donor and recipient antigens bloodtypes.
 33. The method of claim 27 wherein compatibility is achieved when the donor blood does not contain any antigens not expressed by the recipient.
 34. An organization comprising: a first entity which provides identities of donors selected to have particular antigen bloodtypes as determined by testing and analysis of genetic determinants compatible to those of specific recipients, the entity engaged in managing a list of candidate donors so as to balance the number of prospective candidate donors tested and analyzed with the anticipated average number of requests for particular antigen donor bloodtypes received; second entities engaged in collecting blood from donors and processing, storing and distributing blood products derived from donors identified by the first entity; and wherein the first entity charges the second entities for the identities of specific donors and participates in the proceeds from the sale by said second entities of blood products derived from said specific donors.
 35. The organization of claim 34 wherein the first entity and the second entities interact through the internet, thereby permitting the placement of requests by second entities to first entities;
 36. The organization of claim 34 wherein the first entity has separate functional components or affiliated entities for monitoring and analyzing requests received and for recruiting and testing prospective donors in accordance with its management policy. 